Computational Design of Anti-Cancer Molecules: Designing Molecular Mimetics to Hinder Cancer Cell Pro-Survival Mechanisms Using Computer Science, Engineering, Biophysics, and Biochemistry

By D.S. Dalafave.

Published by The Design Collection

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Article: Print $US10.00
Article: Electronic $US5.00

This research focuses on computational molecular design for possible anticancer applications. Computer-based design is an interdisciplinary field which draws on computer science, biophysics, engineering, and biochemistry. It has sped up research by decreasing the need for often expensive and time-consuming experiments. Programmed cell death (apoptosis) is an essential cellular process. Its malfunction can cause cancer and other diseases. Proteins that regulate apoptosis can be either pro-death or pro-survival. Pro-death protein Noxa binds pro-survival protein Mcl-1 and allows apoptosis to proceed. Cells with overexpressed Mcl-1 do not respond properly to Noxa and resist apoptosis, leading to resistance to conventional cancer therapies.
Mimetics are designed molecules, which mimic the function of cell proteins. Noxa mimetics were computationally designed to bind Mcl-1, and thus allow apoptosis. Experimental Noxa structure was used as a template to design putative peptide mimetics in Deep View program. Mcl-1 made the most stable complex with peptide Ala-Glu-Asp-Pro-Pro-Glu-Phe, with the binding energy of -4.8 kcal/mol. Putative small-molecule mimetics were designed in ArgusLab program. Mimetics C₃₂H₁₆N₁₀ and C₃₂H₁₆QN₁₀ (Q = Ga, N, P, S, Se) made stable complexes with Mcl-1, but also with pro-survival proteins Bfl-1 and Bcl-w. A drug based on these mimetics may be useful in fighting cancers with multiple overexpressed pro-survival proteins. A single drug would likely be more economical and better tolerated by patients than several drugs targeting individual proteins. Experimental studies are needed to determine the utility of the putative mimetics for clinical applications. Computational drug design is a rapidly developing field that has a vast potential to enable drug design to ultimately treat almost any illness.

Keywords: Computational Design, Peptide Design, Anticancer Drug Design, Design of Small Molecules for Anticancer Applications

Design Principles and Practices: An International Journal, Volume 4, Issue 2, pp.173-182. Article: Print (Spiral Bound). Article: Electronic (PDF File; 744.536KB).

D.S. Dalafave

Associate Professor, Physics Department, The College of New Jersey, Ewing, New Jersey, USA

The Author got her Ph.D in Physics from Florida State University. Her research in superconductivity received a U.S. patent. Currently, Dr. Dalafave is an Associate Professor in the department of physics at The College of New Jersey. Her duties include teaching and designing courses; carrying out a productive research program; and performing service to the college, profession and community. Dr. Dalafave’s primary research interests are in biophysics, specifically in computational molecular design. She presented at national and international conferences and published in refereed professional journals. She has supervised student research projects that led to international/regional/local presentations and refereed publications.

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